Duplications within exon 1 of TNFRSF11A encoding receptor activator of nuclear factor-kappa B (RANK) are associated with tendon avulsion

Introduction: Different length in-frame duplications within exon 1 of TNFRSF11A encoding receptor activator of nuclear factor-kappa B (RANK) increase osteoclast action and cause rapid turnover bone disease. Complications include deafness, fractures, immobilization hypercalcemia, tooth resorption, and painful skeletal deformities. We investigated two siblings and their father and an unrelated girl with this autosomal dominant dento-osseous phenotype who suffered tendon avulsions. Patients: A 13-year-old boy, his 16-year-old sister, and their 43-year-old father, all with hearing loss and progressive tooth root resorption, have a heterozygous 27-bp duplication within exon 1 of TNFRSF11A. Within 3 years, the siblings suffered seven tendon avulsions with minimal trauma, including the distal Achilles, triceps, and quadriceps tendons. Alendronate was given weekly, which decreased bone turnover markers (BTMs) and treated mild immobilization hypercalcemia following tendon repairs. Their father suffered an Achilles tendon avulsion without a clear mechanism at 20 years of age. An unrelated 10-year-old girl with hearing loss and progressive tooth root resorption was heterozygous de novo for a 12-bp duplication within exon 1 of TNFRSF11A. Alendronate was given weekly. At age 15 years, she bilaterally avulsed her triceps while playing volleyball and then avulsed her Achilles tendon two months later. Conclusions: Tendon avulsion seems to be a complication of constitutive RANK activation from select duplications of TNFRSF11A, but its precise pathogenesis and the impact of bisphosphonate therapy remain uncertain. Bisphosphonate therapy can treat or prevent associated immobilization hypercalcemia and decrease BTMs in people with constitutive RANK activation from such mutations.